6520241NCGCIL2000qHTS of IL-2 Activators: SummaryThe adaptive immune response against any infectious agent begins with the activation of an antigen specific T cell. This relatively rare and inert ("naive") T cell undergoes a massive proliferative expansion and differentiation process to generate sufficient number of potent pathogen-specific effector T cells. The effector T cells fight the infection by making cytokines and helping other cells to become fully armed as well. If any naive T cell has antigen receptors (TCRs) that can be activated by self peptides, then a variety of regulatory mechanisms kick in to prevent this cell from performing to its full potential. These processes collectively constitute the phenomenon of immunological tolerance and their failure leads to autoimmunity. One arm of tolerance involves generation of biochemical negative feedback downstream of the TCR (tuning). This is especially relevant to self antigens present in the body over long periods of time (chronic), which form the bulk of our proteome. The negative feedback serves to tune the TCR signaling, such that the ambient antigenic stimulation is nullified intracellularly. Unfortunately, this critical machinery serves as a target for chronic viral, bacterial and parasitic infections (as well as tumors), which can evade a robust immune response, simply by allowing T cells to tune down their signaling to pathogen or malignancy derived antigens. As such, disrupting the tuning in such cases would allow the tolerant T cell to function again and deliver a robust effector response.If a therapeutic can restore responsiveness to the tuned down T cell, even for a short time, they could combat the pathogen without any additional immunization. To that end, we have developed a sensitive HTS T cell based assay based on IL-2. This assay will be screened against the Molecular Libraries Small Molecule Repository (MLSMR) to find small molecules that could elicit this response.NIH Chemical Genomics Center [NCGC]NIH Molecular Libraries Probe Centers Network [MLPCN]MLPCN Grant: MH096572Assay Submitter (PI): Ron Schwartz, NIAIDPlease see linked AIDs for a detailed protocolThis project is ongoing and will be updated at a later point.6520252interleukin-2 precursor [Mus musculus]71106531Mus musculushouse mousetaxon100903MH0965722